Recent experience in humans and animal models suggests that immune intervention could be extremely beneficial for individuals already infected with human immunodeficiency virus type 1 (HIV). The overall goal of the proposed Research Program Project is to test a new vaccine approach in a therapeutic clinical trial setting. Vaccine vectors derived from Venezuelan equine encephalitis virus (VEE) will first be tested for safety in a placebo controlled Phase I dose escalation trial. The vaccine will then be used to induce and/or enhance immunity to HIV infected patients successfully being treated with highly active anti-retroviral therapy (HAART), potentially allowing these individuals to exert immune control over their infections without the necessity of an expensive life-long drug regimen fraught with side effects and the generation of drug resistant mutants. Project 1 will provide molecular biology support for the clinical trial. We will 1) Design and construct the first generation VEE-based vaccine for the clinical trial, 2) Analyze virus isolates from the trial participants, thus gaining information on virus evolution under drug and immune selection which may inform the design of future therapeutic vaccines, and 3) Test several potential immunogen improvements that could be part of a second generation vaccine design.